title: AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats.
abstract: The pathogenesis of hepatic encephalopathy is multifactorial, involving gut-derived toxins such as ammonia, which has been demonstrated to induce oxidative stress. Therefore, a primary hepatic encephalopathy treatment target is reducing ammonia production in the gastrointestinal tract. AST-120, an oral adsorbent of engineered activated carbon microspheres with surface areas exceeding 1600 m2/g, acts as a sink for neurotoxins and hepatotoxins present in the gut. We evaluated the capacity of AST-120 to adsorb ammonia in vitro and to lower blood ammonia, oxidative stress and brain edema in cirrhotic rats. Cirrhosis was induced in rats by bile duct ligation for 6 weeks. AST-120 was administered by gavage preventively for 6 weeks (0.1, 1, and 4 g/kg/day). In addition, AST-120 was evaluated as a short-term treatment for 2 weeks and 3 days (1 g/kg/day) and as a sink to adsorb intravenously infused ammonium acetate. In vitro, AST-120 efficiently adsorbed ammonia. Ammonia levels significantly decreased in a dose-dependent manner for all AST-120-treated bile duct-ligated rats (nontreated: 177.3 ± 30.8 μM; AST-120, 0.1 g/kg/day: 121.9 ± 13.8 μM; AST-120, 1 g/kg/day: 80.9 ± 30.0 μM; AST-120, 4 g/kg/day: 48.8 ± 19.6 μM) and significantly correlated with doses of AST-120 (r = -0.6603). Brain water content and locomotor activity normalized after AST-120 treatments, whereas arterial reactive oxygen species levels remained unchanged. Furthermore, AST-120 significantly attenuated a rise in arterial ammonia after ammonium acetate administration (intravenously).
  
  
  CONCLUSIONS
  AST-120 treatment decreased arterial ammonia levels, normalized brain water content and locomotor activity but did not demonstrate an effect on systemic oxidative stress. Also, AST-120 acts as an ammonia sink, efficiently removing blood-derived ammonia. Additional studies are warranted to evaluate the effects of AST-120 on hepatic encephalopathy in patients with advanced liver disease.
authors.affiliation: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Bosoi
authors.forename: Christian
authors.initials: C
authors.lastname: Parent-Robitaille
authors.forename: Keith
authors.initials: K
authors.lastname: Anderson
authors.forename: Mélanie
authors.initials: M
authors.lastname: Tremblay
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Rose
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000009:adverse effects; D000641:Ammonia / Q000097:blood*; D000818:Animals; D001652:Bile Ducts / Q000601:surgery*; D001929:Brain Edema / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D002244:Carbon / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008026:Ligation / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000150:complications* / Q000209:etiology*; D008297:Male; D008863:Microspheres; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000085:Acetates; D010087:Oxides; D002244:Carbon; D000641:Ammonia; C040896:AST 120; C018824:ammonium acetate